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OBJECTIVE: Pediatric asthma management faces challenges in medication delivery through oral inhalation devices. While dry powder inhalers (DPIs) are increasingly prescribed to children, many do not receive their prescribed dosage due to insufficient inspiratory flow. This study investigates the utilization of metered-dose inhalers (MDIs) and DPIs among pediatric patients with asthma, focusing on medication delivery challenges. METHODS: Two survey cohorts comprising a total of 42 caregivers of patients with asthma were conducted. Modifications in the second cohort addressed neutral Likert scale responses to obtain more nuanced feedback. RESULTS: Caregivers expressed concerns about uncertainties in their child's ability to use both MDIs and DPIs and challenges in ensuring proper dosage. Notably, 42% of caregivers in the second cohort rated their child's inhaler usage as unable, indicating a significant worry about the efficacy of current delivery methods. Additionally, 50% of caregivers across both cohorts expressed uncertainties about their child receiving the full medication dosage. In response to identified challenges with DPIs, an adaptor device emerged as a potential solution, with caregivers exhibiting positive perceptions post-exposure. Features prioritized for the device include ease of use and assurance of dose delivery. CONCLUSIONS: The study highlights caregiver preferences and the need for innovations to ensure effective medication delivery for pediatric asthma patients. A DPI adaptor device shows promise in addressing technical issues and alleviating caregiver concerns, ultimately contributing to more effective asthma management. Future research should refine these devices based on caregiver feedback to meet the evolving needs of the pediatric asthma population.

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The inhaled delivery of lactic acid bacteria (LAB) probiotics has been demonstrated to exert therapeutic benefits to the lungs due to LAB's immunomodulatory activities. The development of inhaled probiotics formulation, however, is in its nascent stage limited to nebulized LAB. We developed a dry powder inhaler (DPI) formulation of lactobacillus rhamnosus GG (LGG) intended for bronchiectasis maintenance therapy by spray freeze drying (SFD). The optimal DPI formulation (i.e., LGG: mannitol: lactose: leucine = 35: 45: 15: 5 wt.%) was determined based on the aerosolization efficiency (86% emitted dose and 26% respirable fraction) and LGG cell viability post-SFD (7 log CFU/mL per mg powder). The optimal DPI formulation was evaluated and compared to lyophilized naked LGG by its (1) adhesion capacity and cytotoxicity to human lung epithelium cells (i.e., A549 and 16HBE14o- cells) as well as its (2) effectiveness in inhibiting the growth and adhesion of Pseudomonas aeruginosa to lung cells. The optimal DPI of LGG exhibited similar non-cytotoxicity and adhesion capacity to lung cells to naked LGG. The DPI of LGG also inhibited the growth and adhesion of P. aeruginosa to the lung cells as effectively as the naked LGG. The present work established the feasibility of delivering the LAB probiotic by the DPI platform without adversely affecting LGG's anti-pseudomonal activities.

RESUMEN

Ivermectin (IVM), a drug originally used for treating parasitic infections, is being explored for its potential applications in cancer therapy. Despite the promising anti-cancer effects of IVM, its low water solubility limits its bioavailability and, consequently, its biological efficacy as an oral formulation. To overcome this challenge, our research focused on developing IVM-loaded lipid polymer hybrid nanoparticles (LPHNPs) designed for potential pulmonary administration. IVM-loaded LPHNPs were developed using the emulsion solvent evaporation method and characterized in terms of particle size, morphology, entrapment efficiency, and release pattern. Solid phase characterization was investigated by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Using a Twin stage impinger (TSI) attached to a device, aerosolization properties of the developed LPHNPs were studied at a flow rate of 60 L/min, and IVM was determined by a validated HPLC method. IVM-loaded LPHNPs demonstrated spherical-shaped particles between 302 and 350 nm. Developed formulations showed an entrapment efficiency between 68 and 80% and a sustained 50 to 60% IVM release pattern within 96 h. Carr's index (CI), Hausner ratio (HR), and angle of repose (θ) indicated proper flowability of the fabricated LPHNPs. The in vitro aerosolization analysis revealed fine particle fractions (FPFs) ranging from 18.53% to 24.77%. This in vitro study demonstrates the potential of IVM-loaded LPHNPs as a delivery vehicle through the pulmonary route.

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Dry powder inhalers (DPIs) are state-of-the-art pulmonary drug delivery systems. This article explores the transformative impact of nanotechnology on DPIs, emphasizing the Quality Target Product Profile (QTPP) with a focus on aerodynamic performance and particle characteristics. It navigates global regulatory frameworks, underscoring the need for safety and efficacy standards. Additionally, it highlights the emerging field of nanoparticulate dry powder inhalers, showcasing their potential to enhance targeted drug delivery in respiratory medicine. This concise overview is a valuable resource for researchers, physicians, and pharmaceutical developers, providing insights into the development and commercialization of advanced inhalation systems.

Asunto(s)

Sistemas de Liberación de Medicamentos , Inhaladores de Polvo Seco , Inhaladores de Polvo Seco/métodos , Humanos , Administración por Inhalación , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/química , Pulmón/metabolismo , Pulmón/efectos de los fármacos , Nanomedicina/métodos , Tamaño de la Partícula , Nanotecnología/métodos

RESUMEN

Magnesium stearate (MgSt) and lactose fines are often used as ternary components in carrier-based dry powder inhalers (DPIs) to improve fine particle fraction (FPF), but whether they act synergistically to improve aerosolization performance of DPI formulations is currently less studied. In addition, the applicability of utilizing powder rheological parameters to predict the FPF needs to be further verified. Thus, in this study, using fluticasone propionate (FP) as a model drug, effect of lactose fines addition in 0.5% MgSt containing DPI formulations on their powder and aerodynamic properties was explored. Influence of MgSt and fines mixing order on the DPIs performance was also investigated. The results showed that addition of lactose fines (1-10%) in 0.5% MgSt containing formulations could further improve flowability and enhance adhesion of the mixtures, and they could act synergistically to improve FPF. Moreover, the presence of 0.5% MgSt can greatly reduce the amount of lactose fines required to achieve the comparable FPF. The mixing order can affect distribution of MgSt on the carrier surface, with higher FPF noted when MgSt was mixed with carrier first, followed by lactose fines. A good linear relationship between powder rheological parameters such as basic flowability energy (BFE), Permeability and FPF was disclosed. In conclusion, in FP based DPIs, MgSt and lactose fines act synergistically to enhance FPF by tuning powder characteristics. Good flowability (27.39%) and strong adhesion (72.61%) contributed to the enhanced drug deposition in the lung.

Asunto(s)

Aerosoles , Inhaladores de Polvo Seco , Fluticasona , Lactosa , Tamaño de la Partícula , Polvos , Ácidos Esteáricos , Lactosa/química , Fluticasona/química , Fluticasona/administración & dosificación , Polvos/química , Ácidos Esteáricos/química , Excipientes/química , Reología , Composición de Medicamentos/métodos , Administración por Inhalación , Química Farmacéutica/métodos , Broncodilatadores/administración & dosificación , Broncodilatadores/química

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Pulmonary delivery of antibiotics is an effective strategy in treating bacterial lung infection for cystic fibrosis patients, by achieving high local drug concentrations and reducing overall systemic exposure compared to systemic administration. However, the inherent anatomical lung defense mechanisms, formulation characteristics, and drug-device combination determine the treatment efficacy of the aerosol delivery approach. In this study, we prepared a new tobramycin (Tobi) dry powder aerosol using excipient enhanced growth (EEG) technology and evaluated the in vitro and in vivo aerosol performance. We further established a Pseudomonas aeruginosa-induced lung infection rat model using an in-house designed novel liquid aerosolizer device. Notably, novel liquid aerosolizer yields comparable lung infection profiles despite administering 3-times lower P. aeruginosa CFU per rat in comparison to the conventional intratracheal administration. Dry powder insufflator (e.g. Penn-Century DP-4) to administer small powder masses to experimental animals is no longer commercially available. To address this gap, we developed a novel rat air-jet dry powder insufflator (Rat AJ DPI) that can emit 68-70 % of the loaded mass for 2 mg and 5 mg of Tobi-EEG powder formulations, achieving a high rat lung deposition efficiency of 79 % and 86 %, respectively. Rat AJ DPI can achieve homogenous distribution of Tobi EEG powder formulations at both loaded mass (2 mg and 5 mg) over all five lung lobes in rats. We then demonstrated that Tobi EEG formulation delivered by Rat AJ DPI can significantly decrease CFU counts in both trachea and lung lobes at 2 mg (p < 0.05) and 5 mg (p < 0.001) loaded mass compared to the untreated P. aeruginosa-infected group. Tobi EEG powder formulation delivered by the novel Rat AJ DPI showed excellent efficiencies in substantially reducing the P. aeruginosa-induced lung infection in rats.

Asunto(s)

Antibacterianos , Inhaladores de Polvo Seco , Polvos , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Ratas Sprague-Dawley , Tobramicina , Animales , Tobramicina/administración & dosificación , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/efectos de los fármacos , Administración por Inhalación , Antibacterianos/administración & dosificación , Ratas , Aerosoles , Pulmón/microbiología , Masculino , Excipientes/química

RESUMEN

Invasive pulmonary aspergillosis (IPA) is a fatal fungal infection with a high mortality rate. Voriconazole (VCZ) is considered a first-line therapy for IPA and shows efficacy in patients for whom other antifungal treatments have been unsuccessful. The objective of this study was to develop a high-potency VCZ-loaded liposomal system in the form of a dry-powder inhaler (DPI) using the spray-drying technique to convert liposomes into a nanocomposite microparticle (NCMP) DPI, formulated using a thin-film hydration technique. The physicochemical properties, including size, morphology, entrapment efficiency, and loading efficiency, of the formulated liposomes were evaluated. The NCMPs were then examined to determine their drug content, production yield, and aerodynamic size. The L3NCMP was formulated using a 1:1 lipid/L-leucine ratio and was selected for in vitro studies of cell viability, antifungal activity, and stability. These formulated inhalable particles offer a promising approach to the effective management of IPA.

RESUMEN

Dry powder inhalers (DPIs) are widely employed to treat respiratory diseases, offering numerous advantages such as high dose capacity and stable formulations. However, they usually face challenges in achieving sufficient pulmonary drug delivery and minimizing excessive oropharyngeal deposition. This review provides a new viewpoint to address these challenges by focusing on the role of swirling flow, a crucial yet under-researched aspect that induces strong turbulence. In the review, we comprehensively discuss both key classic designs (tangential inlet, swirling chamber, grid mesh, and mouthpiece) and innovative designs in inhalers, exploring how the induced swirling flow initiates powder dispersion and promotes delivery efficiency. Valuable design considerations to effectively coordinate inhalers with formulations and patients are also provided. It is highlighted that the delicate manipulation of swirling flow is essential to maximize benefits. By emphasizing the role of swirling flow and its potential application, this review offers promising insights for advancing DPI technology and optimizing therapeutic outcomes in inhaled therapy.

Asunto(s)

Sistemas de Liberación de Medicamentos , Inhaladores de Polvo Seco , Diseño de Equipo , Humanos , Administración por Inhalación , Pulmón/metabolismo , Animales

Asunto(s)

Antiasmáticos , Asma , Sistemas de Liberación de Medicamentos , Desarrollo de Medicamentos , Nanomedicina , Humanos , Asma/tratamiento farmacológico , Antiasmáticos/administración & dosificación , Antiasmáticos/uso terapéutico , Animales , Nanopartículas , Investigación Biomédica Traslacional

RESUMEN

INTRODUCTION: Dry powder inhaler (DPI) formulations are gaining attention as universal formulations with applications in a diverse range of drug formulations. The practical application of DPIs to pulmonary drugs requires enhancing their delivery efficiency to the target sites for various treatment modalities. Previous reviews have not explored the relation between particle morphology and delivery to different pulmonary regions. This review introduces new approaches to improve targeted DPI delivery using novel particle design such as supraparticles and metal-organic frameworks based on cyclodextrin. AREAS COVERED: This review focuses on the design of DPI formulations using polysaccharides, promising excipients not yet approved by regulatory agencies. These excipients can be used to design various particle morphologies by controlling their physicochemical properties and manufacturing methods. EXPERT OPINION: Challenges associated with DPI formulations include poor access to the lungs and low delivery efficiency to target sites in the lung. The restricted applicability of typical excipients contributes to their limited use. However, new formulations based on polysaccharides are expected to establish a technological foundation for the development of DPIs capable of delivering modalities specific to different lung target sites, thereby enhancing drug delivery.

Asunto(s)

Sistemas de Liberación de Medicamentos , Inhaladores de Polvo Seco , Excipientes , Pulmón , Polisacáridos , Polvos , Humanos , Polisacáridos/química , Administración por Inhalación , Pulmón/metabolismo , Excipientes/química , Tamaño de la Partícula , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/química , Composición de Medicamentos/métodos , Animales , Química Farmacéutica , Estructuras Metalorgánicas/química

RESUMEN

Background: Asthma controller medications can be delivered via pressurized metered dose inhaler (pMDI) or dry powder inhaler (DPI) devices. Objective: This study aimed to evaluate the frequency of exacerbations and satisfaction rate with device use in asthmatics using pMDIs or DPIs. Methods: A multicenter, cross-sectional study was conducted in adults who used pMDIs or DPIs with correct inhaler technique and good adherence for asthma treatment. Demographic and asthma-related characteristics of the subjects and data regarding device satisfaction were collected through a face-to-face interview in the outpatient clinic. Rates of pMDI and DPI users and the data were compared between the two groups. Results: The study included 338 patients (mean age: 48.6 ± 14.5 years, 253 [74.9%] women). Among participants, 96 (28.4%) were using pMDI and 242 (71.6%) were using DPI. The age of patients using pMDI were significantly lower compared with DPI users. No significant difference was observed in terms of device satisfaction and clinical outcomes of asthma between pMDI and DPI users with good inhaler technique and good adherence. Conclusion: More asthmatics use DPIs, however, pMDIs are used in younger asthmatic patients. No significant difference in terms of device satisfaction and clinical outcomes of asthma was observed between pMDI and DPI users.

RESUMEN

Dry powder inhalers (DPIs) are the first choice for inhalation drug development. However, some conventional DPI formulation processes require heating, which may damage high molecular weight drugs such as proteins and nucleic acids. In this study, we propose a novel DPI preparation process that avoids the use of heat. Dry powders were prepared by cryomilling nanofiber mats composed of polyvinyl alcohol, D(-)-mannitol (Man), and α-chymotrypsin (α-Chy) as the model drug using the electrospinning method. The addition of Man conferred high dispersibility and excellent in vitro aerosol performance to the nanofiber mat powder in a very short milling time (less than 0.5 min) as assessed using the Andersen cascade impactor. Powders were classified according to the degree of friability, and among these, nanofiber mats containing 15 % Man and milled for 0.25 min exhibited the highest aerosol performance. Nanofiber mats containing Man milled for less than 0.5 min also exhibited greater α-Chy enzymatic activity than a nebulized α-Chy solution. Furthermore, single inhalation induced no significant lung tissue damage as evidenced by lactate dehydrogenase activity assays of mouse bronchoalveolar lavage fluid. This novel DPI formulation process may facilitate the safe and efficient inhalational delivery of therapeutic proteins.

Asunto(s)

Aerosoles , Quimotripsina , Manitol , Nanofibras , Nanofibras/química , Nanofibras/administración & dosificación , Animales , Administración por Inhalación , Manitol/química , Quimotripsina/química , Ratones , Inhaladores de Polvo Seco , Alcohol Polivinílico/química , Polvos , Sistemas de Liberación de Medicamentos , Pulmón/metabolismo , Líquido del Lavado Bronquioalveolar/química , Masculino

RESUMEN

BACKGROUND: Patients with cystic fibrosis commonly suffer from lung infections caused by Pseudomonas aeruginosa. Recently, the Levofloxacin (LVF) nebulizing solution (Quinsair®) has been prescribed for the antimicrobial management. The sustained-release (SR) dry powder formulation of LVF is a convenient alternative to Quinsair®. It has the potential to enhance patient convenience and decrease the likelihood of drug resistance over time. OBJECTIVE: In this paper, we set forth to formulate and evaluate the potential application of sodium alginate (SA) and sodium carboxymethylcellulose (SCMC) for sustained pulmonary delivery of LVF. METHODS: The spray-dried (SD) LVF microparticles were formulated using SCMC and SA along with L-leucine (Leu). The microparticles were analyzed in terms of particle size, morphology, x-ray diffraction (XRD), in-vitro drug release, and aerodynamic properties. Selected formulations were further proceeded to short-term stability test. RESULTS: The polymer-containing samples displayed process yield of 33.31%-39.67%, mean entrapment efficiency of 89% and volume size within the range of 2-5 µm. All the hydrogel microparticles were amorphous and exhibited rounded morphology with surface indentations. Formulations with a drug-to-excipient ratio of 50:50 and higher, showed a 24-h SR. The aerodynamic parameters were fine particle fraction and emitted dose percentage ranging between 46.21%-60.6% and 66.67%-87.75%, respectively. The short-term stability test revealed that the formulation with a 50:50 drug-to-excipient ratio, containing SA, demonstrated better physical stability. CONCLUSION: The selected formulation containing SA has the potential to extend the release duration. However, further enhancements are required to optimize its performance.

RESUMEN

Delivering novel antimycobacterial agents through the pulmonary route using nanoparticle-based systems shows promise for treating diseases like tuberculosis. However, creating dry powder inhaler (DPI) with suitable aerodynamic characteristics while preserving nanostructure integrity and maintaining bioactivity until the active ingredient travels deeply into the lungs is a difficult challenge. We developed DPI formulations containing levofloxacin-loaded solid lipid nanoparticles (SLNs) via spray-drying technique with tailored aerosolization characteristics for effective inhalation therapy. A range of biophysical techniques, including transmission electron microscopy, confocal microscopy, and scanning electron microscopy were used to measure the morphologies and sizes of the spray-dried microparticles that explored both the geometric and aerodynamic properties. Spray drying substantially reduced the particle sizes of the SLNs while preserving their nanostructural integrity and enhancing aerosol dispersion with efficient mucus penetration. Despite a slower uptake rate compared to plain SLNs, the polyethylene glycol modified formulations exhibited enhanced cellular uptake in both A549 and NR8383 cell lines. The percent viability of Mycobacterium bovis had dropped to nearly 0 % by day 5 for both types of SLNs. Interestingly, the levofloxacin-loaded SLNs demonstrated a lower minimum bactericidal concentration (0.25 µg/mL) compared with pure levofloxacin (1 µg/mL), which indicated the formulations have potential as effective treatments for tuberculosis.

Asunto(s)

Antituberculosos , Inhaladores de Polvo Seco , Levofloxacino , Nanopartículas , Tamaño de la Partícula , Tuberculosis , Levofloxacino/administración & dosificación , Levofloxacino/química , Levofloxacino/farmacología , Nanopartículas/química , Administración por Inhalación , Humanos , Antituberculosos/administración & dosificación , Antituberculosos/química , Antituberculosos/farmacología , Antituberculosos/farmacocinética , Tuberculosis/tratamiento farmacológico , Lípidos/química , Mycobacterium bovis/efectos de los fármacos , Línea Celular , Aerosoles , Células A549 , Animales , Secado por Pulverización , Pruebas de Sensibilidad Microbiana , Portadores de Fármacos/química , Polietilenglicoles/química , Antibacterianos/administración & dosificación , Antibacterianos/química , Antibacterianos/farmacología , Liposomas

RESUMEN

BACKGROUND: This study aimed to describe the use of pressurized metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs) in Spanish subjects in terms of sociodemographic, clinical, and functional characteristics in subjects with asthma or COPD on maintenance treatment with inhaled therapy. METHODS: This was a retrospective, descriptive, national, multi-center, and observational study using a database with 1.8 million patients from hospitals and primary care centers as a secondary information source. RESULTS: The sample included 24,102 subjects with asthma on maintenance therapy (26.0% with pMDI, 55% with DPI, and 19.0% with a combination of DPI + pMDI inhalers) and 12,858 subjects with COPD on maintenance therapy (26% with pMDI; 39% with DPI; and 35% with a combination of pMDI + DPI inhalers, mostly extemporary triple therapy). In proportion, subjects ≥ 75 y old used more pMDI than DPI, while younger subjects (40-64 y old) used more DPI. An inhalation chamber was prescribed in 51.0% of subjects with asthma and 47.2% of subjects with COPD treated with pMDI. The use of an inhalation chamber increases with the degree of air-flow limitation by disease and age. In subjects with comorbidities, pMDI inhaler use increased in those ≥ 75 y old for subjects with asthma and subjects with COPD. Switching from pMDI to DPI and vice versa was relatively common: 25% of subjects with asthma and 21.6% of subjects with COPD treated with pMDI had switched from DPI in the previous year. On the contrary, 14.1% and 11.4% of subjects with asthma and subjects with COPD, respectively, treated with DPI had switched from pMDI the last year. CONCLUSIONS: The use of pMDI or DPI can vary according to age, both in asthma and COPD. Switching from pMDI to DPI and vice versa is relatively common. Despite the availability of dual- and triple-therapy inhalers on the market, a considerable number of subjects were treated with multiple devices.

RESUMEN

Dry-powder inhalers (DPIs) are valued for their stability but formulating them is challenging due to powder aggregation and limited flowability, which affects drug delivery and uniformity. In this study, the incorporation of L-leucine (LEU) into hot-melt extrusion (HME) was proposed to enhance dispersibility while simultaneously maintaining the high aerodynamic performance of inhalable microparticles. This study explored using LEU in HME to improve dispersibility and maintain the high aerodynamic performance of inhalable microparticles. Formulations with crystalline itraconazole (ITZ) and LEU were made via co-jet milling and HME followed by jet milling. The LEU ratio varied, comparing solubility, homogenization, and aerodynamic performance enhancements. In HME, ITZ solubility increased, and crystallinity decreased. Higher LEU ratios in HME formulations reduced the contact angle, enhancing mass median aerodynamic diameter (MMAD) size and aerodynamic performance synergistically. Achieving a maximum extra fine particle fraction of 33.68 ± 1.31% enabled stable deep lung delivery. This study shows that HME combined with LEU effectively produces inhalable particles, which is promising for improved drug dispersion and delivery.

RESUMEN

Introduction: Identifying factors influencing peak inspiratory flow (PIF) is essential for aerosol drug delivery in stable patients with chronic obstructive pulmonary disease. While a minimum PIF for dry powder inhalers (DPIs) is established, acute bronchodilator (BD) effects on PIF remain unknown. Materials and Methods: An inspiratory flow meter (In-Check™ DIAL) was used to measure PIF in stable patients during a 24-week observational cross-sectional study. Additionally, bronchodilator responsiveness (BDR) was determined using the In-Check DIAL device and spirometry. Patients received four puffs of albuterol, and pre- and post-BD PIF, forced expiratory volume in one second (FEV1), and forced vital capacity were measured. Sixty-three patients completed acute BDR data collection from July 31, 2019, to November 9, 2021. Primary endpoints were pre- and post-BD spirometry and PIF. Statistical analyses included PIF correlations with FEV1. BD change was assessed according to inhaler resistance and sex (subgroup analysis). Results: Median patient age was 64.8 years, 85.7% were non-Hispanic White, and 57.1% were female. The median increase in absolute PIF (In-Check DIAL) was 5.0 L/min, and the % PIF change was 8.9%. With albuterol, 57.1% experienced a PIF BD change >5.0%, whereas 49.2% experienced a change >10.0%. Similarly, 55.6% experienced an FEV1 BD change >5.0% and 28.6% had a >10.0% FEV1 BD change with albuterol. PIF was weakly correlated with FEV1 BD change (absolute; % PIF; r = 0.28 [p = 0.02]; r = 0.21 [p = 0.11]). Pre- and post-BD median PIF were 75.5 and 83.5 L/min for low-to-medium-resistance DPI and 45.0 and 52.0 L/min for high-resistance, respectively. The median increases in pre- and post-BD PIF were 9.0 L/min in males and 4.5 L/min in females. In contrast to when using the In-Check DIAL device, we observed no consistent bronchodilatory effects on PIF measured by spirometry. Conclusions: Using the In-Check DIAL device, ∼50% of patients experienced >10% PIF increase after acute BD, potentially enhancing medication lung deposition. Further research is required to understand PIF's impact on medication delivery. ClinicalTrials.gov Identifier: NCT04168775.

Asunto(s)

Albuterol , Broncodilatadores , Inhaladores de Polvo Seco , Enfermedad Pulmonar Obstructiva Crónica , Espirometría , Humanos , Masculino , Femenino , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Persona de Mediana Edad , Anciano , Estudios Transversales , Broncodilatadores/administración & dosificación , Administración por Inhalación , Albuterol/administración & dosificación , Volumen Espiratorio Forzado , Aerosoles , Capacidad Vital , Inhalación/fisiología

RESUMEN

Although inhalation therapy represents a promising drug delivery route for the treatment of respiratory diseases, the real-time evaluation of lung drug deposition remains an area yet to be fully explored. To evaluate the utility of the photo reflection method (PRM) as a real-time non-invasive monitoring of pulmonary drug delivery, the relationship between particle emission signals measured by the PRM and in vitro inhalation performance was evaluated in this study. Symbicort® Turbuhaler® was used as a model dry powder inhaler. In vitro aerodynamic particle deposition was evaluated using a twin-stage liquid impinger (TSLI). Four different inhalation patterns were defined based on the slope of increased flow rate (4.9-9.8 L/s2) and peak flow rate (30 L/min and 60 L/min). The inhalation flow rate and particle emission profile were measured using an inhalation flow meter and a PRM drug release detector, respectively. The inhalation performance was characterized by output efficiency (OE, %) and stage 2 deposition of TSLI (an index of the deagglomerating efficiency, St2, %). The OE × St2 is defined as the amount delivered to the lungs. The particle emissions generated by four different inhalation patterns were completed within 0.4 s after the start of inhalation, and were observed as a sharper and larger peak under conditions of a higher flow increase rate. These were significantly correlated between the OE or OE × St2 and the photo reflection signal (p < 0.001). The particle emission signal by PRM could be a useful non-invasive real-time monitoring tool for dry powder inhalers.

Asunto(s)

Inhaladores de Polvo Seco , Pulmón , Tamaño de la Partícula , Inhaladores de Polvo Seco/métodos , Pulmón/metabolismo , Administración por Inhalación , Sistemas de Liberación de Medicamentos/métodos , Aerosoles , Polvos , Liberación de Fármacos

RESUMEN

Purpose: This phase 1 study (NCT04370873) evaluated safety and pharmacokinetics/pharmacodynamics (PK/PD) of MK-5475 in participants with pulmonary hypertension associated with COPD (PH-COPD). Methods: Eligible participants were 40-80 years old with COPD (FEV1/FVC <0.7; FEV1 >30% predicted) and PH (mean pulmonary arterial pressure ≥25 mmHg). Participants were randomized 2:1 to MK-5475 or placebo via dry-powder inhaler once daily for 7 days in Part 1 (360 µg) or 28 days in Part 2 (380 µg). Safety was assessed by adverse events (AEs) and arterial blood oxygenation. Part-2 participants had pulmonary vascular resistance (PVR; primary PD endpoint) and pulmonary blood volume (PBV; secondary PD endpoint) measured at baseline and Day 28. A non-informative prior was used to calculate posterior probability (PP) that the between-group difference (MK-5475 - placebo) in mean percent reduction from baseline in PVR was less than -15%. Results: Nine participants were randomized in Part 1, and 14 participants in Part 2. Median age of participants (86.4% male) was 68.5 years (41-77 years); 95.5% had moderate-to-severe COPD. Incidences of AEs were comparable between MK-5475 and placebo: overall (5/14 [36%] versus 5/8 [63%]), drug-related (1/14 [7%] versus 2/8 [25%]), and serious (1/14 [7%] versus 1/8 [13%]). MK-5475 caused no meaningful changes in arterial blood oxygenation or PBV. MK-5475 versus placebo led to numerical improvements from baseline in PVR (-21.2% [95% CI: -35.4, -7.0] versus -5.4% [95% CI: -83.7, 72.9]), with between-group difference in PVR less than -15% and calculated PP of 51%. Conclusion: The favorable safety profile and numerical reductions in PVR observed support further clinical development of inhaled MK-5475 for PH-COPD treatment.

Asunto(s)

Hipertensión Pulmonar , Pulmón , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Masculino , Anciano , Administración por Inhalación , Femenino , Persona de Mediana Edad , Resultado del Tratamiento , Método Doble Ciego , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/diagnóstico , Adulto , Pulmón/fisiopatología , Pulmón/efectos de los fármacos , Anciano de 80 o más Años , Guanilil Ciclasa Soluble/metabolismo , Inhaladores de Polvo Seco , Factores de Tiempo , Volumen Espiratorio Forzado , Activadores de Enzimas/administración & dosificación , Activadores de Enzimas/efectos adversos , Activadores de Enzimas/farmacocinética , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Antihipertensivos/farmacocinética , Presión Arterial/efectos de los fármacos , Capacidad Vital

RESUMEN

Lung diseases have received great attention in the past years because they contribute approximately one-third of the total global mortality. Pulmonary drug delivery is regarded as one of the most appealing routes to treat lung diseases. It addresses numerous drawbacks linked to traditional dosage forms. It presents notable features, such as, for example, a non-invasive route, localized lung drug delivery, low enzymatic activity, low drug degradation, higher patient compliance, and avoiding first-pass metabolism. Therefore, the pulmonary route is commonly explored for delivering drugs both locally and systemically. Inhalable nanocarrier powders, especially, lipid nanoparticle formulations, including solid-lipid and nanostructured-lipid nanocarriers, are attracting considerable interest in addressing respiratory diseases thanks to their significant advantages, including deep lung deposition, biocompatibility, biodegradability, mucoadhesion, and controlled drug released. Spray drying is a scalable, fast, and commercially viable technique to produce nanolipid powders. This review highlights the ideal criteria for inhalable spray-dried SLN and NLC powders for the pulmonary administration route. Additionally, the most promising inhalation devices, known as dry powder inhalers (DPIs) for the pulmonary delivery of nanolipid powder-based medications, and pulmonary applications of SLN and NLC powders for treating chronic lung conditions, are considered.